The need for developing ever more efficacious methods of treating peripheral vascular disease (PVD) which, like coronary artery disease (CAD), is the progressive narrowing of the arterial tree by the atherosclerotic process. These diseases result in diminished blood flow to vital organs and extremities beyond the site of narrowing or occlusion: Diabetes mellitus (DM) is a major contributor to such disease processes, as are a large number of other well-known health risks and factors, such as elevated levels of cholesterol. As the prevalence of these factors increases, so does that of PVD and CAD. For example, PVD affects an estimated 27 million people in Europe and North America, and it produces significant morbidity and mortality in those populations. An estimated 10.5 million of those affected are symptomatic while 16.5 million are asymptomatic. Despite the prevalence of PVD, it is estimated that only 25% of symptomatic patients are currently treated for the disease.
PVD typically affects multiple segments of a given artery. Short segments of severe narrowing are typically treated with catheter-based techniques such as angioplasty and the placement of one or more stents. When there is severe narrowing over a long segment or involving multiple arteries within a limb, surgical revascularization is the treatment of choice. When this is insufficient, particularly in the diabetic population, limb amputation is indicated, and an estimated 60,000 are performed annually in the United States. Severe narrowing within the vessel or related causes of poor blood flow commonly result in the formation of intra-arterial thrombus (clot) formation, which, if not immediately corrected, will lead to the death of tissue and the need for amputation of the host limb. Endovascular catheter placement for the delivery of a thrombolytic agent to dissolve the clot is efficacious, but commonly requires days of drug infusion, intensive care monitoring, and frequent trips to a radiology suite to reposition the catheter.
Systemic administration of therapeutic agents allows for wide-spread distribution of these agents throughout the body. The function of the therapeutic agent depends upon the uptake of the medication by the targeted organ and upon the agent's pharmacokinetics which determine its concentration as a function of time. However, with systemic delivery, non-targeted organs may be adversely affected by the medication, and this can cause potentially serious side-effects. Consequently, the efficacy of the therapeutic agents at the target site can be limited by both its concentration at the site of interest and by its toxicity in other non-targeted organs.
The clinical benefits of site-specific catheter-based delivery systems for the administration of therapeutics can include increased safety, increased efficacy, reduced toxicities, more reliable therapeutic drug levels, and decreased and simplified dosing requirements. Safety, efficacy and toxicity are all independent but related parameters in the pharmacokinetics of each therapeutic agent. Site-specific drug delivery into the target tissue ensures that the majority of the drug goes to the site it is intended to act upon with minimal or at least small and tolerable effect upon non-targeted tissue, thereby decreasing the effects of toxicity. This allows for higher concentrations of the therapeutic agent to be administered to the targeted site, thereby increasing the efficacy of the agent. An additional benefit of site-specific delivery of therapeutic agents is that the patient receives a smaller cumulative dose, thereby further reducing the overall risk to the patient.
Site-specific catheter-based drug delivery allows local administration of therapeutic agents and reliable therapeutic drug levels to be achieved and maintained because systemic clearance is reduced. By obtaining reliable therapeutic drug levels in this manner, dosing requirements are decreased and simplified. As mentioned above, local drug levels can be maintained at higher levels than could be achieved with systemic administration because systemic toxicity is reduced with local delivery.
A site-specific drug-delivery catheter is also required when active biologic agents are being administered to a focal site of injury. As an example, site-specific delivery of thrombolytic therapy to the site of a clot in the vascular tree of an ischemic limb is preferred to systemic delivery. With site-specific delivery, a high local concentration of the thrombolytic agent can be delivered to achieve lysis of the clot material at the site of infusion, whereas, systemic delivery of a thrombolytic therapy could lead to generalized bleeding at multiple remote sites.
An emerging modality for the treatment of PVD is site-specific stem cell therapy for the treatment of ischemic limbs. This cellular therapy has demonstrated efficacy in the formation of new blood vessels in ischemic limbs of patients with PVD in a recently published randomized controlled clinical study. The increasing population of patients with DM and PVD potentially makes this a very large market.
One alternative that can obviate the problem of washout of the thrombolytic agent downstream from the lesion is to occlude the artery with a blockage means such as a balloon placed distally from the lesion being treated. While effective over brief periods intra-operatively, this approach does limit the time over which the agent can act, because downstream arterial occlusion cannot be maintained indefinitely without ischemic injury to dependent tissues and organs. These problems arise not only with the catheter-based delivery of thrombolytics, but also when delivering new and emerging classes of agents such as stem cell suspensions and angiogenesis factors.
These clinical needs have driven many substantial efforts aimed at catheter development over the past several years, and a variety of devices has been designed as a result. Generally speaking, the most interesting class of devices is that which incorporates internal channels or create pathways that allow blood flow past the lesion while drugs or other therapies are being delivered to the lesion either through a balloon that is integral to the catheter or from ports elsewhere on it. Integral balloons can also be used to carry out angioplasty on the lesion or to temporarily block the artery during drug delivery to the lesion. Within the medical device community, such catheters are often referred to as perfusion sleeves, and there is a large literature on the topic. For a succinct overview of the spectrum of catheters that includes some of these devices see Yang (Yang X: Imaging of Vascular Gene Therapy. Radiol. 228:36-49, 2003, of which is hereby incorporated by reference herein in its entirety) who lists several of the commercially available systems now being employed for the image-based delivery of intravascular gene therapies.
A frequent use of perfusion sleeve devices is within the context of percutaneous transluminal angioplasty, although applications for them in a variety of other interventions have been conceived, clinically tested, and put into routine use as well. An early multiple-cuff catheter with windows on the shaft to shunt the arterial blood flow past the treatment zone was described by Baran et al. (Baran O E, Baran A O D: Multiple Surgical Cuff. U.S. Pat. No. 4,423,725, 1984, of which is hereby incorporated by reference herein in its entirety). Others are those of Schweich et al. (Schweich Jr. C J, Harrison K D, Burns M M: Blood Perfusion Catheter. U.S. Pat. No. 5,716,340, 1998, of which is hereby incorporated by reference herein in its entirety), who introduced a perfusion-shunt channel via an inflatable balloon wound toroidally around the catheter shaft, and Macoviak et al. (Macoviak J A, Samson W J, Leary J J, Esch B D: Perfusion Shunt Apparatus and Method. U.S. Pat. No. 6,139,517, 2000, of which is hereby incorporated by reference herein in its entirety), who developed a stand-alone shunt apparatus that could be mounted on a catheter for use in the aortic arch. Lary (Lary B G: Passive Perfusion Sleeve/Placement Catheter Assembly. U.S. Pat. No. 6,506,180, 2003, of which is hereby incorporated by reference herein in its entirety) incorporated a specially designed inflation lumen for the perfusion sleeve's angioplasty balloon.
Several types of perfusion sleeve devices have also been designed for drug delivery simultaneous with balloon angioplasty. One such catheter described in the literature for this purpose was the “infusion sleeve” system of Moura et al. (Moura A, Jules Y T, Lam M D, Hébert D, Kermode J R, Grant G W, Robitaille D, Klein E J, Yock P G, Simpson J B, Kaplan A V: Intramural Delivery of Agent via a Novel Drug-Delivery Sleeve. Circulation 92:2299-2305, 1995, of which is hereby incorporated by reference herein in its entirety), which was used for applications such as the delivery of heparin to lesions on the arterial wall (Kaplan A V, Vandormael M, Hofmann M, Weil H J, Störger H, Krajcar M, Gallant P, Simpson J B, Reifart N: Heparin Delivery at the Site of Angioplasty with a Novel Drug Delivery Sleeve. Am. J. Cardiol. 77:307-310, 1996, of which is hereby incorporated by reference herein in its entirety). A variant of it that was optimized specifically for perfusion capabilities was introduced in 1998 (Cannan C R, Kaplan V A, Klein E J, Galant P, Sharaf B L, Williams D O: Novel Perfusion Sleeve for Use During Balloon Angioplasty: Initial Clinical Experience. Catheteriz Cardiovasc. Diag. 44:358-362, 1998, of which is hereby incorporated by reference herein in its entirety) and subsequently used in angioplasty procedures. Examples of some other more recent flow bypass devices include those described by Evans et al. (Evans M A, Demarais D M, Eversull C S, Leeflang S A: System and Methods for Clot Dissolution. U.S. Pat. No. 6,663,613, 2003, of which is hereby incorporated by reference herein in its entirety) and Zadno-Azizi et al. (Zadno-Azizi G R, Patel M R, Muni K P, Bagaosian C J, Ha H V: Method for Containing and Removing Occlusions in the Carotid Arteries. U.S. Pat. No. 6,970,204, 2004, of which is hereby incorporated by reference herein in its entirety).
A general and consistent limitation of the prior art is that, among other things, the bulk of the design work on this class of catheters has been done without detailed assessment of the flows by reference to Computational Fluid Dynamics (CFD) or to experiments performed on scaled up physical platforms that retain geometrical and dynamical similarity with the catheters. Instead, much of the modeling has been far more empirical in nature, relying typically on observations with prototype devices, and with the design iterations then made largely on the basis of those results. This is a perfectly valid approach and has been used, for example, to investigate side-slit versus side-hole geometries for drug delivery ports on intravascular pulse-spray catheters (Cho K J, Recinella D K: Pattern of Dispersion from a Pulse-Spray Catheter for Delivery of Thrombolytic Agents. Acad. Radiol. 4:210-216, 1997, of which is hereby incorporated by reference herein in its entirety). On the other hand, the total cross-sectional area of a 3 mm inner-diameter artery is only 7 mm2, thus restricting the catheter cross section to perhaps 5 mm2 or less, for such an artery. Therefore, the real estate available for a balloon inflation lumen, a drug delivery lumen, a perfusion bypass lumen, a guidewire channel, etc. is very limited. As a result, biomedical engineers have often had to introduce complex multi-purpose channels into their catheter designs in order to circumvent this limitation.